Efficient electrochemical synthesis of robust, densely functionalized water soluble quinones

Article abstract of DOI:10.1039/c9cc08878d

Conjugate addition of thiols to benzoquinones has been coupled to in situ electrochemical oxidation of the resulting hydroquinone to enable full substitution of quinone C-H bonds. The sulfonated thioether-substituted quinones exhibit high solublity and st

Full text of DOI:10.1039/c9cc08878d

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10.1039/C9CC08878D.
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DOI: 10.1039/C9CC08878D
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Efficient Electrochemical Synthesis of Robust,
Densely Functionalized Water Soluble Quinones
James B. Gerken,a Alexios Stamoulis,a Sung-Eun Suh,a Nicholas D. Fischer,a Yeon J. Kim,a Ilia A.
Guzei,a and Shannon S. Stahla*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
O
Conjugate addition of thiols to benzoquinones have been coupled
to in situ electrochemical oxidation of the resulting hydroquinone
to enable full substitution of quinone C–H bonds. The sulfonated
thioether-substituted quinones exhibit high solublity and stability
in aqueous solution and have redox potentials ranging from 440–
750 mV vs. SHE. The electrosynthetic protocol is effective on >100
g scale.
NaO3S
NaO3S
S
S
S
S
SO3Na
SO3Na
1
O
a) Previous Approach 1: Addition/elimination reactions of chloranil
O
O
Limitations:
RS
RS
SR
SR
Cl
Cl
Cl
Cl
increased substrate cost
RSSR byproduct formation
low yield
+ 4 RSH
– 4 HCl
HX waste
O
O
b) Previous Approach 2: Sequential oxidative functionalization of BQ using BQ as a stoichiometric oxidant
Highly-stable, water soluble quinones are important targets
for energy-related applications, such as redox flow batteries
and mediated electrolysis.1-3 We recently reported the design of
a tetrasubstituted quinone containing four sulfonated thioether
O
OH
O
OH
OH
O
O
SR
SR
SR
SR
+ RSH
+ RSH
HO
OH
H2Q
O
OH
O
BQ
moieties (1, Scheme 1) that displays substantially enhanced
OH
O
O
O
O
O
O
SR
SR
SR
SR
+
RSH
stability relative to less substituted quinones of similar redox
potential.4,5 Quinones with anionic groups feature improved
aqueous solubility and membrane impermeability. The
thioether-tethered sulfonates were identified as a particularly
conveniently installed anionic group,4 and substitution at all
positions on the quinone ring significantly enhances the stability
of the quinone. The thioether linkage is robust with respect to
substitution in aqueous acid at elevated temperatures over
prolonged periods. Herein, we describe an electrosynthetic
RS
HO
OH
HO
OH
OH
O
OH
OH
O
O
O
O
Limitations:
RS
RS
RS
RS
SR
SR
RS
RS
SR
+ RSH
tedious multistep protocol
low yield
significant H2Q waste
SR
SR
HO
OH
O
c) Present Approach: iterative conjugate addition/electrochemical oxidation
– 2 e–
– 2 H+
O
O
Advantages:
scalable
RS
RS
SR
SR
high yields
atom-economical (only H2 as waste)
straightforward one-step protocol
4 RSH
+
protocol that provides efficient and scalable access to
1
and a
series of other substituted quinones.
O
O
In previous work, we pursued the synthesis of
1 using two
Scheme 1. Addition/elimination and conjugate-addition/oxidation routes to substituted
thioether quinones together with a new addition-electrooxidation protocol for quinone
thioetherification.
established methods.4 The first employed addition/elimination
reactions with chloranil, involving nucleophilic substitution of
the chloride substituents by thiols (Scheme 1a).6 The low yield
of desired product obtained from this protocol, however,
prompted us to evaluate a conjugate addition/oxidation
sequence (Scheme 1b). Thiols are particularly effective
nucleophiles for conjugate addition to benzoquinone (BQ),7,8
and the hydroquinone obtained from nucleophilic addition can
be oxidized by unreacted BQ. This process may be repeated
until the quinone is fully substituted, ultimately enabling the
synthesis of tetrathioether hydroquinones.4,9 The resulting
reaction mixture, however, contains significant quantities of
hydroquinone (at least 4 equiv) and/or partially substituted
quinone byproducts, complicating product isolation and limiting
the yield of the desired product. These issues motivated efforts
to identify an alternative synthetic protocol that could be used
to prepare substituted quinones. The data outlined below show
that electrochemical oxidation methods allow for effective
a. Department of Chemistry, University of Wisconsin-Madison, 1101 University
Avenue, Madison, Wisconsin 53706, USA. E-mail: stahl@chem.wisc.edu.
‡ Electronic Supplementary Information (ESI) available: [Synthetic procedures, NMR
spectra, crystal structures, cyclic voltammetry data]. See DOI: 10.1039/x0xx00000x
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synthesis of thioether-substituted quinones starting from either ions as are consumed at the cathode. Very slow convection (i.e.,
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DOI: 10.1039/C9CC08878D
no stirring) is necessary because quinones formed at the anode
quinones or hydroquinones.
Benzoquinones are susceptible to conjugate addition at ring are transported to the cathode and reduced quickly relative to
carbons bearing C–H bonds to form functionalized the rate at which they react with thiols, leading to lower current
hydroquinones.10 The resulting hydroquinones can undergo efficiency. It was possible to scale the reactions in ordinary
electrochemical oxidation to the corresponding benzoquinones
a)
at potentials determined by their substituents.11
O
Electrochemical oxidation of hydroquinones and catechols in
SR
the presence of nucleophiles has been demonstrated previously
O
to form substituted quinone products,12–15 but this process
commonly leads to addition of a single nucleophile due to the
higher reduction potential of the quinone following nucleophile
addition.16 Addition of a thiol, however, lowers the potential of
the resulting thioether quinone by approximately 20 mV. This
insight provides the basis for an electrochemical approach to
achieve complete thioetherification of the C–H positions in BQ
and other substituted BQ derivatives by conducting the
electrolysis of the quinone in the presence of a sulfonated alkyl
thiols (Scheme 2a). Use of this class of nucleophiles is especially
felicitous since the sulfonate group and its counterion may
serve as the supporting electrolyte for the electrochemical
reaction.17
RS
SR
SR
SR
O
O
O
SR
O
O
O
4
RSH
RSH
3
RSH
2
RSH
1
- 2e–
+
OH
SR
OH
OH
SR
SR
OH
OH
OH
SR
SR
OH
OH
RS
RS
RS
SR
SR
–
R =
SO3
> 100 g scale
Initial voltammetry experiments showed that the sodium
mercaptoethylsulfonate (MESNa) nucleophile exhibited no
redox behavior at a glassy carbon electrode at the potential of
the H2Q/BQ redox couple at pH 1. Therefore, bulk electrolysis
experiments were conducted with reticulated vitreous carbon
(RVC) as the anode material (Table 1). Acidic conditions were
employed (pH 1) to favour H2 evolution as the cathodic reaction.
Constant potential electrolysis was performed at a potential
chosen to ensure complete oxidation of the hydroquinone that
formed during the oxidative coupling reaction. An initial
experiment was conducted by stirring 4 equiv of MESNa and BQ,
with an RVC anode and Pt wire counter electrode. Considerable
charge was passed but negligible conversion was apparent. This
failure was traced to the use of stirring, as the same experiment
conducted with a lack of stirring led to nearly quantitative
product formation (Entries 1 vs. 2). Because minor variations in
the electrode potential did not have a deleterious effect on the
product yield (Entries 2 and 3), the electrolysis was then
conducted under constant current using currents similar to
those observed in the constant potential experiments (Entries 4
and 5). Larger scale reactions (≥ 10 g) made it impractical to use
Pt wire; however, Ni wire proved to be an effective counter
- e-
RVC anode
b)
OH
OH
Ni wire cathode
RS
RS
SR
SR
+
4 equiv RSH
pH 2 H2SO4 in 9:1 H2O:EtOH
rt, unstirred
OH
OH
0.2 M
1: 95% (100 g scale)
2: 98% (10 g scale)
–
–
SO3
SO3
1: R =
2: R =
c)
d)
Scheme 2. a) Electrochemical synthesis of 1 and 2; b) Proposed reaction sequence
enabling the scalable synthesis of tetrathioether quinones; c) Synthesis apparatus
(power supply, electrodes, beaker); d) typical isolated product.
Table 1. Reaction Condition Screening and Scale-up.a
electrode.
Finally,
the
reaction
sodium
Entry
Product
E / I
Conditions
A, stirred
F.E. (%)b
--c
93
n.d.d
100
n.d.
93
Yield (%)
mercaptopropylsulfonate (MPSNa) was conducted on 100 g
scale, using H2Q as the substrate to avoid exposure to BQ (Entry
6). As the reaction was scaled up, the substrate concentration
was kept constant while the sizes of the electrodes were
proportionately increased, and the current was increased to
keep the reaction time roughly constant. Excellent yields of
1
2
3
4
5
6
2
2
2
2
1
1
800 mV
800 mV
860 mV
820 mV
35 mA
--c
98
97
98
96
95
A
A
B
B
C
310 mA
a Conditions: Undivided cell, RVC working electrode, pH 1. A - 0.3 M benzoquinone,
1.2 M thiol, Pt wire C.E., 3–4 mmol scale. B - 0.25 M benzoquinone, 1 M thiol, Ni
wire C.E., 10 g scale. C - 0.25 M hydroquinone, 1 M thiol, Ni wire C.E., 100 g scale.
Faradaic Efficiency Cyclic voltammetry analysis of the reaction solution before
and after the passage of 4 F/mol exhibited no change. d not determined
tetrathioether quinones
1 and 2 were obtained under the
optimized, constant current conditions (Scheme 2b; see ESI‡ for
details).
b
c
Several considerations account for the success of these
reactions. In an undivided cell, the pH remains constant,
because the anode reaction produces the same quantity of H+
2 | J. Name., 2012, 00, 1-3
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laboratory glassware using a simple power supply to prepare course of the reaction. Although excess thiol was VrieewquAritriceledOdnluinee
≥10–100 g of the desired quinones (Scheme 2c,d).
to formation of disulphide by-product (D6OeI:q1u0i.v10o39f/CR9SCHC, 0r8a8t7h8eDr
The slow mass transport, which is necessary to avoid than the theoretical amount of 2 equiv), the desired product
unproductive redox cycling, leads to significant concentration was obtained in 86% yield. In the case of , selectivity was
9
gradients during the electrolysis, evident by the colour of the achieved by increasing the pH. At higher pH, enough thiolate is
quinone intermediates. The anodic oxidation reaction could formed that nucleophilic addition and C–S bond formation is
involve the starting hydroquinone, an intermediate thioether favoured over competing S–S bond formation. In this manner,
hydroquinone, or the tetrasubstituted hydroquinone product. quinone
9 was obtained from catechol in pH 7.5, 0.1 M
Additional redox reactions may take place away from the phosphate buffer.18 In general, it is noteworthy that the
electrode to produce a substituted quinone that can react with reactions afford the observed thioether products despite the
a thiol. This combination of anodic and solution-phase fact that the benzoquinone reduction potentials can be >500
processes afford quinone derivatives that are eventually mV higher than typical disulphide reduction potentials (for
converted into the fully substituted product.
reduction potentials of the starting materials, see Table S1).11,19
Varying the thiol and quinone or hydroquinone starting Presumably, this selectivity arises from the much more facile
materials enabled the synthesis of a series of different thioether electrochemical kinetics for hydroquinone oxidation than thiol
quinone products. The yields of these compounds are dimerization at a carbon electrode.
summarized in Scheme 3, together with their redox potentials
and their aqueous solubilities. Low-potential quinones, such as (poly)sulfonate is straightforward in most cases. The electrolysis
the precursors to and 10, react more slowly with thiols. To is performed at concentrations near the solubility limit of the
Isolation of the reaction products as a salt of a
3
avoid side reactions, these products were synthesized via product (Scheme 3 and Table S1), and the product typically
electrolysis with constant potential rather than constant precipitates in high purity on dilution of the reaction mixture
current (see ESI‡ for details). The synthesis of
3
was begun from with a water-miscible, but less polar solvent, such as ethanol or
the quinone. Side reactions with solvent during the reactive acetone. The traces of incompletely substituted products or
dissolution of (cf. step 1 in Scheme 2b) prior to electrolysis led starting material, being less charged, are more soluble in the
to insoluble material and presumably account for the lower mixed solvent and are removed by filtration.
3
yield of
3.
Some additional observations emerging from the
Higher potential quinones, such as the precursors to
8
and preparation of these derivatives are worth noting. If the
9
, are effective H-atom abstracting agents and open a pathway hydroquinone is poorly soluble in water, it can be advantageous
to formation of disulphide by-products, competing with the to use a mixed solvent system. This approach was used in the
desired nucleophilic addition reactions with thiols. Thus, synthesis of , and 10, which employed acetone as a co-
3, 6
modified conditions were required to generate acceptable solvent. Complete solubility of the hydroquinone is not
yields of conjugate addition products instead of quinone- necessary; only enough is required to allow the desired current
catalyzed disulphide formation. In the case of 8, it was possible to pass. Further dissolution is facilitated by formation of more
to access the product by slowly adding the thiol during the
soluble products that can undergo reoxidation to soluble
quinones. These quinones can then mediate redox reactions
with the starting hydroquinone to a quinone that undergoes
reactive dissolution with the thiol. In recalcitrant cases (e.g., 2-
phenylhydroquinone), it is advantageous to start with the
quinone so that the process begins with the reactive dissolution
OH
OH
OH
OH
OH
RS
SR SR'
SR'
RS
Ph
RS
Me
RS
Me
SR
RS
SR SR'
SR'
RS
SR
RS
Me
Me
OH
OH
OH
OH
OH
1: 95%a
605 mV
0.32 M
2: 98%b
618 mV
0.58 M
3: 60%c
643 mV
0.97 M
4: 85%
559 mV
0.55 M
5: 99%
634 mV
0.19 M
OH
OH
OH
OH
O
to form
a
more-soluble product that can undergo
Me
RS
Me
SR
Me
RS
Me
Me
RS
CF3 RS
OH
SR
SR
SR
electrochemical formation of the remaining thioethers. This
tactic is opposite to the one employed by Nematollahi and
Tammari, in which the lower solubility of the reaction product
was used to achieve selective mono-thioetherification.13
CF3
SR
RS
OH
OH
OH
SR
O
6: 84%
578 mV
2.01 M
7: 91%
518 mV
0.94 M
8: 86%
703 mV
0.19 M
9: 41%
754 mV
0.65 M
10: 100%c
439 mV
0.27 M
–
–
SO3
SO3
R' =
R =
7
6
2
1
3
5
9
10
4
8
400
500
600
E (mV vs. SHE)
700
800
Scheme 3. Isolated yields, reduction potentials, and aqueous solubilities of
electrosynthesized hydroquinone products. a100 g scale, b10 g scale, cconstant potential
electrolysis. General reaction conditions: H2Q (10 mmol), RSH 1.1n equiv (n = # of
equivalents needed for full substitution), 0.2 M in H2O/EtOH (See ESI‡ for details).
Figure 1. A molecular drawing of 2 asymmetric units of the crystal structure showing
the structure of the quinone form of 2 drawn with 50% probability ellipsoids.
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J. Name., 2013, 00, 1-3 | 3
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On extended electrolysis, the fully substituted product is at appealing targets for energy storage and conVvieewrsAiroticnle, Oanlninde
DOI: 10.1039/C9CC08878D
least partially oxidized to the corresponding quinone. Redox mediated electrolysis applications.
cycling of this quinone back to the hydroquinone at the cathode
prevents the electrode potential from rising to a point where
decomposition reactions become fast. The quinone form of 2,
Conflicts of interest
obtained by running the electrolysis reaction for longer than
usual, led to the formation of crystals that were suitable for X-
ray crystallographic analysis. The X-ray data are in accord with
the proposed product (Figure 1). Similar crystallographic
The authors have filed patents on some of the compounds and
methods described herein.
support for the structure of compound
1 was obtained in the
Acknowledgements
hydroquinone oxidation state (see Figure S4 and ESI‡ for
details). Although most of the compounds described in this
paper are thermodynamically capable of the 2-electron
reduction of O2, this process appears to be kinetically facile only
in the case of the naphthoquinone derivative. Thus, the isolated
product is typically the hydroquinone.
Financial support for this work was provided by the Center for
Molecular Electrocatalysis, an Energy Frontier Research Center
funded by the US Department of Energy, Office of Science,
Office of Basic Energy Sciences, and by the Wisconsin Alumni
Research Foundation (WARF) through the WARF Accelerator
Program. NMR spectroscopy facilities were partially supported
by NSF CHE-0342998, NSF CHE-1048642, a UW Madison
Instructional Laboratory Modernization Award, a gift from Paul
J. and Margaret M. Bender, and by NIH S10 OD012245. Mass
spectrometry equipment was partially supported by NIH 1S10
In summary, an efficient electrosynthetic protocol has been
identified for the preparation of densely functionalized, water-
soluble quinones. The successful outcome arises from the use
of thiols that produce substitution products amenable to
reoxidation at potentials tolerated by the nucleophile. The
protocol is compatible with ordinary laboratory glassware, has OD020022-1.
been performed at hectogram scale in high yield, and has been
demonstrated in the functionalization of an array of partially
Notes and references
substituted BQ derivatives. We anticipate that this tactic will
find utility in the preparation of other redox-active organic
molecules, and the products derived therefrom represent
1
2
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3
4
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5
Quinones with ether-linked anionic groups have also found 16 Occasionally, disubstitution is observed, such as in the
utility in flow batteries: Y. Li, M.-A. Goulet, D. A. Pollack, D. G.
Kwabi, S. Jin, D. De Porcellinis, E. F. Kerr, R. G. Gordon, and M. J.
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cyanide via the intercession of an enedione intermediate. See,
for example: G. J. Perry and M. D. Sutherland, Tetrahedron
1982, 38, 1471-1476.
6
7
M. Schubert, J. Am. Chem. Soc. 1947, 69, 712-713.
A. Blackhall and R. H. Thomson, J. Chem. Soc. 1953, 1953, 1138- 17 For a related concept, see: A. F. Roesel, T. Broese, M. Májek and
1143. R. Francke, ChemElectroChem 2019, 6, 4229-4237.
Thiosilanes have been used effectively as well: N. A. Romero, W. 18 Despite the success of these variations, some limitations to the
O. Parker Jr., and T. M. Swager, Macromolecules 2019, DOI:
10.1021/acs.macromol.9b01855.
A. R. Katritzky, D. Fedoseyenko, P. P. Mohapatra and P. J. Steel,
Synthesis 2008, 2008, 777-787.
8
9
method have also been observed. For example, the high
nucleophilicity of the thiol resulted in displacement of
sulphonate, cyano, and trifluoroacetyl groups from quinone
precursors, ultimately, affording low yields of 1.
10 For recent reviews, see: a) B. Hosamani, M. F. Ribeiro, E. N. da 19 W. J. Lees and G. M. Whitesides, J. Org. Chem. 1993, 58, 642-
Silva Jr. and I. N. N. Namboothiri, Org. Biomol. Chem. 2016, 14, 647.
4 | J. Name., 2012, 00, 1-3
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